This is a new application in response to NIDA Program Announcement PAS-08-186 for Medications Development for Polydrug Addiction Treatment. The concurrent use of cocaine + heroin and cocaine + nicotine are prevalent forms of polydrug abuse, and are associated with significant public health problems, including cancer, pulmonary and cardiovascular disease and HIV/AIDS. We developed the first preclinical model of cocaine + heroin (speedball) addiction, and now we propose to develop a new polydrug model of cocaine + nicotine abuse. These two models will be used to identify and evaluate medications for the treatment of dual addiction to cocaine in combination with heroin or nicotine. Polydrug abuse involving two or more drugs is a complex treatment challenge, and often the effectiveness of a medication is not predictable from its known pharmacology. To facilitate translation of the most effective treatment approaches into clinical practice, we propose to evaluate a pharmacologically diverse series of medications that are FDA approved for other indications. These medications include anxiolytics, antidepressants, nicotinic partial agonists, stimulants, and an opioid mixed agonist antagonist. Each medication has been shown to reduce the abuse-related effects of cocaine, heroin, or nicotine alone in clinical or preclinical studies. We hypothesize that medications that effectively reduce cocaine self-administration may also be effective in reducing the abuse-related effects of cocaine in combination with nicotine or heroin. Well-validated behavioral procedures are proposed to evaluate the effects of these medications on the abuse-related effects of cocaine and polydrug combinations of cocaine + heroin or nicotine. Drug discrimination procedures will be used to characterize the potency, time-course and stimulus characteristics of polydrug combinations, and candidate treatment medications. In drug self-administration studies, medications will be administered chronically to model clinical treatment programs. Chronic treatment is necessary to determine the stability of medication effects, the severity and duration of any adverse side effects, and to monitor possible medication withdrawal signs when treatment is discontinued. The selectivity of medication effects will be determined with a second-order schedule of drug- and food-maintained responding. The abuse liability of the most effective medications will also be examined. A progressive-ratio procedure will be used to compare the relative effectiveness of treatment medications as well as the extent to which the reinforcing efficacy of polydrug combinations is altered. These multi-disciplinary studies will facilitate translation of novel polydrug abuse medications into clinical treatment.